crossing96/oncoscreening huggingface dataset:
Prescribing trend of pioglitazone after safety warning release in Korea.	OBJECTIVES: This study was conducted to determine the number of pioglitazone users before and after the issue of the pioglitazone safety warning (intervention) by South Korea's Ministry of Food and Drug Safety on June 10, 2011. STUDY DESIGN: A quasi-experimental interrupted time series study was conducted to examine the number of pioglitazone and other antidiabetic drug users between 2009 and 2015. METHODS: We used the National Health Insurance Service-National Sample Cohort database to estimate the number of pioglitazone and other antidiabetic drug users between 2009 and 2015. Relative and absolute changes in the number of drug users were calculated with 95% CIs. Monthly numbers of drug users were presented according to the maximum likelihood estimation method, and a segmented regression analysis was performed to evaluate the effect of the intervention. A Durbin-Watson statistic and Dickey-Fuller test were used to assess autocorrelation and seasonality, respectively. RESULTS: A total of 80,724 patients with diabetes, including 12,249 pioglitazone users, were investigated. The relative change in pioglitazone users was -8.13% (95% CI, -8.41% to -7.86%). The intervention was associated with an immediate decrease of 177 pioglitazone users per 1000 patients with diabetes (P <.05). Without this intervention, the predicted proportion of pioglitazone users would be 90 per 1000 patients with diabetes, which is 1.5-fold higher than the actually observed rate of 60 per 1000 patients with diabetes. CONCLUSIONS: This intervention led to a moderate decrease in pioglitazone users. Until further evidence is available, caution should be exercised when prescribing pioglitazone to patients with high potential risk of bladder cancer and alternative treatments should be considered.	bladder
CircZFR serves as a prognostic marker to promote bladder cancer progression by regulating miR-377/ZEB2 signaling.	Circular RNAs (circRNAs) have been identified as crucial regulators of gene expression in human cancer biology. CircZFR is a novel identified circRNA and its effect in bladder cancer remains unclearly. In the present study, we aimed to investigate the role of circZFR in the progression of bladder cancer. First, we demonstrated that the expression of circZFR was higher in bladder cancer tissues and cells compared with adjacent non-tumor tissues and normal bladder epithelial cells. And higher circZFR levels were positively correlated with bladder cancer patients' pathological T stage, grade, lymphatic metastasis, recurrence, progression-free survival (PFS) and overall survival (OS). Functionally, knockdown of circZFR could significantly prohibit cell growth, migration and invasion, arrest cell cycle as well as promote apoptosis of bladder cancer cells in vitro study. Mechanistically, we observed that circZFR could directly bind to miR-377 as sponge to promote ZEB2 expression in bladder cancer cells. In addition, rescue assays demonstrated that restoration of ZEB2 significantly impaired the suppressive effects of circZFR silencing on bladder cancer cells growth, migration and invasion. Taken together, our results illuminated that circZFR could be a prognostic biomarker in bladder cancer and exerted oncogenic roles through regulating miR-377/ZEB2 axis in bladder cancer, which indicated that circZFR could be a potential therapeutic target for bladder cancer patients treatment.	bladder
Pembrolizumab versus chemotherapy in recurrent, advanced urothelial cancer in Japanese patients: a subgroup analysis of the phase 3 KEYNOTE-045 trial.	BACKGROUND: The open-label, randomized, active-controlled KEYNOTE-045 study (NCT02256436) showed that second-line pembrolizumab significantly improved overall survival (OS) of patients with advanced/metastatic urothelial cancer (UC) that progressed after first-line platinum-containing chemotherapy, compared with standard chemotherapy (paclitaxel, docetaxel, or vinflunine). Pembrolizumab is approved for patients with bladder cancer in Japan. PATIENTS AND METHODS: Analysis was performed in the subgroup of Japanese patients enrolled in the KEYNOTE-045 study. Coprimary end points were OS and progression-free survival (PFS). Objective response rate (ORR) and safety were secondary end points. RESULTS: Fifty-two Japanese patients (pembrolizumab, n = 30; chemotherapy, n = 22) were followed up for a median of 26.1 months. Patients who received pembrolizumab compared with chemotherapy had a 19% lower risk for death (hazard ratio [HR] 0.81, 95% CI 0.44-1.50); after adjusting for baseline covariates, the HR for OS was 0.61 (95% CI 0.32-1.15). The 24-month OS rate was higher with pembrolizumab (26.9% vs 14.3%). PFS was 2.0 and 4.9 months for pembrolizumab and chemotherapy, respectively (HR 1.71, 95% CI 0.95-3.08). ORR was similar for pembrolizumab and chemotherapy (20.0% vs 18.2%); durability of response was higher with pembrolizumab: 67% and 33% of patients, respectively, maintained a response for > 12 months. Treatment-related adverse events, including grade 3-5 events, occurred less frequently with pembrolizumab. CONCLUSIONS: Pembrolizumab provided durable antitumor activity in patients with locally advanced/metastatic UC that progressed after platinum-containing chemotherapy in the overall population and in the Japanese subgroup; safety profile was consistent with that previously observed for pembrolizumab.	bladder
Robotic versus open radical cystectomy throughout the learning phase: insights from a real-life multicenter study.	BACKGROUND AND OBJECTIVES: Robot-assisted radical cystectomy (RARC) has been shown to be non-inferior to open radical cystectomy (ORC) for the treatment of bladder cancer (BC). However, most data on RARC come from high-volume surgeons at high-volume centers. The objective of the study was to compare perioperative and mid-term oncologic outcomes of RARC versus ORC in a real-life cohort of patients treated by surgeons starting their experience with RARC. MATERIALS AND METHODS: Data were prospectively collected from consecutive patients undergoing RARC and ORC at five referral Centers between 2010 and 2016 by five surgeons (one per center) with no prior experience in RARC. Patients with high-risk non-muscle-invasive or organ-confined muscle-invasive (T2N0M0) bladder cancer were considered for RARC. The main study endpoints were perioperative outcomes, postoperative surgical complications, and mid-term oncologic outcomes. RESULTS: Overall, 124 and 118 patients underwent RARC and ORC, respectively. Baseline patients' and tumors' characteristics were comparable between the two groups. Yet, the proportion of patients receiving neoadjuvant chemotherapy was significantly higher in the RARC cohort. Median operative time was significantly higher, while median EBL, LOH, and transfusion rates were significantly lower after RARC. Median number of lymph nodes removed was significantly higher after RARC. All other histopathological outcomes, as well as the rate of early (< 30 days) and late postoperative complications, were comparable to ORC. At a median follow-up of 2 years, 29 (23%) and 41 (35%) patients developed disease recurrence (p = 0.05), while 20 (16%) and 37 (31%) died of bladder cancer (p = 0.005) after RARC and ORC, respectively. CONCLUSIONS: With proper patient selection, RARC was non-inferior to ORC throughout the surgeons' learning phase. Yet, the observed differences in oncologic outcomes suggest selection bias toward adoption of RARC for patients with more favorable disease characteristics.	bladder
Synthesis, characterization, and biological activity of a triphenylphosphonium-containing imidazolium salt against select bladder cancer cell lines.	Imidazolium salts have shown great promise as anticancer materials. A new imidazolium salt (TPP1), with a triphenylphosphonium substituent, has been synthesized and evaluated for in vitro and in vivo cytotoxicity against bladder cancer. TPP1 was determined to have a GI(50) ranging from 200 to 250 μM over a period of 1 h and the ability to effectively inhibit bladder cancer. TPP1 induces apoptosis, and it appears to act as a direct mitochondrial toxin. TPP1 was applied intravesically to a bladder cancer mouse model based on the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Cancer selectivity of TPP1 was demonstrated, as BBN-induced tumors exhibited apoptosis but normal adjacent urothelium did not. These results suggest that TPP1 may be a promising intravesical agent for the treatment of bladder cancer.	bladder
Adaptive Immune Resistance to Intravesical BCG in Non-Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials.	PURPOSE: To characterize immune cell expression among patients with non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guerin (BCG). EXPERIMENTAL DESIGN: Patients with NMIBC treated with intravesical BCG (2008-2015) were identified, and a tissue microarray was constructed using paired pre- and post-BCG bladder samples. Among patients undergoing BCG, cystoscopic evaluation began 3 months after initiating BCG treatment to determine therapeutic response. IHC was performed for CD8, CD4, FoxP3, PD-L1 (SP-142 and 22C3), and PD-1. A full slide review of PD-L1(+) staining tumors was performed to characterize PD-L1 and CD8 colocalization. RNA-seq was performed on cored tumors from available specimens. We compared immune cell populations between BCG responders and nonresponders, and between pretreatment and postreatment tumor samples. Baseline PD-L1 staining in the BCG naïve population was then validated in a separate cohort. RESULTS: The final cohort contained 63 pretreatment NMIBC cases, including 31 BCG responders and 32 BCG nonresponders. No differences in CD4, CD8, or FoxP3 expression were identified between responders and nonresponders. Baseline PD-L1 expression (22C3 and SP-142) was observed in 25% to 28% of nonresponders and 0% to 4% of responders (P < 0.01). PD-L1(+) cells in BCG nonresponders colocalized with CD8(+) T cells. In addition, BCG therapy did not increase PD-L1 gene expression (RNA-seq) or protein levels (IHC). The number of pretreatment CD4(+) T cells was very low among PD-L1(+) nonresponders (12%) and high among PD-L1(-) nonresponders (50%, P < 0.01). In a separate cohort of 57 patients with NMIBC undergoing BCG, baseline PD-L1 (22C3) staining was similar (26%). CONCLUSIONS: One mechanism of BCG failure may be adaptive immune resistance. Baseline tumor PD-L1 expression predicts an unfavorable response to BCG and if validated, could be used to guide therapeutic decisions.	bladder
Predicting Response to Neoadjuvant Chemotherapy in Bladder Cancer.	CONTEXT: Neoadjuvant chemotherapy (NAC) is recommended prior to radical cystectomy in the setting of muscle-invasive bladder cancer. Despite a 5-10% survival benefit, some patients do not respond to NAC. Identification of the nonresponders could avoid side effects and delay in surgery. OBJECTIVE: The objective of this review is to summarize the latest evidence regarding predictors of NAC response. EVIDENCE ACQUISITION: MEDLINE, Embase, and the Cochrane Library databases were searched for published studies including clinical, pathological, molecular, and imaging tests or factors that can be applied before or during NAC to predict its results. EVIDENCE SYNTHESIS: Patient characteristics and imaging techniques seem to have minimal utility to predict NAC response. Only advanced magnetic resonance imaging techniques seem to have a potential role. There is insufficient evidence to suggest a change in NAC paradigm for variant histology, whereas the most promising results come from molecular characterization of tumors. CONCLUSIONS: No validated instrument currently exists to predict NAC response. While awaiting further evidence, no strong recommendation can be made toward a shift in paradigm. PATIENT SUMMARY: The most effective and aggressive treatment for muscle-invasive bladder cancer is radical cystectomy preceded by effective neoadjuvant chemotherapy. In this paper, we reviewed the current literature and published evidence to identify predictors of response to neoadjuvant chemotherapy for muscle-invasive bladder cancer. To date, no instrument exists to predict which patients will respond to neoadjuvant chemotherapy.	bladder
Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies.	BACKGROUND: Patients with predominant variant histology (VH) of bladder tumors, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited. OBJECTIVE: To evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and VH, enrolled in PURE-01 study (NCT02736266). DESIGN, SETTING, AND PARTICIPANTS: In the open-label, single-arm, phase 2 PURE-01 study, three courses of 200 mg pembrolizumab preceding radical cystectomy (RC) were administered in T2-4aN0M0 MIBC patients. The amended study design included patients with predominant VH. INTERVENTION: Neoadjuvant pembrolizumab and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pathological complete response (pT0) in intention-to-treat population was the primary endpoint. Biomarker analyses included programmed cell-death ligand-1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 antibody) and comprehensive genomic profiling (FoundationOne assay). Multivariable logistic regression analyses (MVAs) evaluated the histological category (predominant VH vs nonpredominant VH vs pure urothelial carcinoma), tumor mutational burden (TMB) and CPS in association with the pathological response. RESULTS AND LIMITATIONS: From February 2017 to June 2019, 114 patients were enrolled; 34 (30%) of them presented with VH, including 19 (17%) with predominant VH. In total, the pT0 rate was 37% (95% confidence interval [CI]: 28-46) and the pT ≤ 1 rate was 55% (95% CI: 46-65). The majority of predominant VH patients presented with squamous-cell carcinoma (SCC; N = 7), and six of seven (86%) had downstaging to pT ≤ 1, with one pT0; two of three lymphoepithelioma-like (LEL) variants had a pT0 response. None of the remaining nine predominant VHs had a response. On MVA, TMB and CPS were associated with both the pT0 and the pT ≤ 1 response, regardless of tumor histology. CONCLUSIONS: The updated PURE-01 results confirm the activity of neoadjuvant pembrolizumab in MIBC. Patients with SCC and LEL features may be suitable for neoadjuvant immunotherapy trials. CPS and TMB are the key response predictors irrespective of the histological subtypes. PATIENT SUMMARY: In the PURE-01 study, we have preliminarily evaluated the activity of neoadjuvant pembrolizumab in patients with predominant variant histology (VH). Of these patients, those harboring squamous-cell carcinoma or a lymphoepithelioma-like variant feature had major, although preliminary, pathological responses compared with those with other predominant VHs. Expression of programmed cell-death ligand-1 and tumor mutational burden may predict the pathological response to pembrolizumab, and provide a rationale for selecting patients according to these features instead of the histological bladder cancer subtypes.	bladder
Papillary urothelial neoplasm of low malignant potential (PUN-LMP): Still a meaningful histo-pathological grade category for Ta, noninvasive bladder tumors in 2019?	BACKGROUND: Papillary urothelial neoplasm of low malignant potential (PUN-LMP) was introduced as a noninvasive, noncancerous lesion and a separate grade category in 1998. Subsequently, PUN-LMP was reconfirmed by World Health Organization (WHO) 2004 and WHO 2016 classifications for urothelial bladder tumors. OBJECTIVES: To analyze the proportion of PUN-LMP diagnosis over time and to determine its prognostic value compared to Ta-LG (low-grade) and Ta-HG (high-grade) carcinomas. To assess the intraobserver variability of an experienced uropathologist assigning (WHO) 2004/2016 grades at 2 time points. MATERIALS AND METHODS: Individual patient data of 3,311 primary Ta bladder tumors from 17 hospitals in Europe and Canada were available. Transurethral resection of the tumor was performed between 1990 and 2018. Time to recurrence and progression were analyzed with cumulative incidence functions, log-rank tests and multivariable Cox-regression stratified by institution. Intraobserver variability was assessed by examining the same 314 transurethral resection of the tumorslides twice, in 2004 and again in 2018. RESULTS: PUN-LMP represented 3.8% (127/3,311) of Ta tumors. The same pathologist found 71/314 (22.6%) PUN-LMPs in 2004 and only 20/314 (6.4%) in 2018. Overall, the proportion of PUN-LMP diagnosis substantially decreased over time from 31.3% (1990-2000) to 3.2% (2000-2010) and to 1.1% (2010-2018). We found no difference in time to recurrence between the three WHO 2004/2016 Ta-grade categories (log-rank, P = 0.381), nor for LG vs. PUN-LMP (log-rank, P = 0.238). Time to progression was different for all grade categories (log-rank, P < 0.001), but not between LG and PUN-LMP (log-rank, P = 0.096). Multivariable analyses on recurrence and progression showed similar results for all 3 grade categories and for LG vs. PUN-LMP. CONCLUSIONS: The proportion of PUN-LMP has decreased to very low levels in the last decade. Contrary to its reconfirmation in the WHO 2016 classification, our results do not support the continued use of PUN-LMP as a separate grade category in Ta tumors because of the similar prognosis for PUN-LMP and Ta-LG carcinomas.	bladder
Cost comparison between open radical cystectomy, laparoscopic radical cystectomy, and robot-assisted radical cystectomy for patients with bladder cancer: a systematic review of segmental costs.	BACKGROUND: Robot-assisted radical cystectomy is becoming a common treatment for bladder carcinoma. However, in comparison with open radical cystectomy, its cost-effectiveness has not been confirmed. Although few published reviews have compared total costs between the two surgical procedures, no study has compared segmental costs and explained their impact on total costs. METHODS: A systematic review was conducted based on studies on the segmental costs of open, laparoscopic, and robot-assisted radical cystectomy using PubMed, Web of Science, and Cochrane Library databases to provide insight into cost-effective management methods for radical cystectomy. The segmental costs included operating, robot-related, complication, and length of stay costs. A sensitivity analysis was conducted to determine the impact of the annual number of cases on the per-case robot-related costs. RESULTS: We identified two studies that compared open and laparoscopic surgeries and nine that compared open and robotic surgeries. Open radical cystectomy costs were higher than those of robotic surgeries in two retrospective single-institution studies, while robot-assisted radical cystectomy costs were higher in 1 retrospective single-institution study, 1 randomized controlled trial, and 4 large database studies. Operating costs were higher for robotic surgery, and accounted for 63.1-70.5% of the total robotic surgery cost. Sensitivity analysis revealed that robot-related costs were not a large proportion of total surgery costs in institutions with a large number of cases but accounted for a large proportion of total costs in centers with a small number of cases. CONCLUSIONS: The results show that robot-assisted radical cystectomy is more expensive than open radical cystectomy. The most effective methods to decrease costs associated with robotic surgery include a decrease in operating time and an increase in the number of cases. Further research is required on the cost-effectiveness of surgeries, including quality measures such as quality of life and quality-adjusted life years.	bladder
Severe and Prolonged Hypotension After Oral 5-Aminolevulinic Acid Administration in a Patient With End-Stage Renal Disease Undergoing Transurethral Resection of a Bladder Tumor: A Case Report.	A 72-year-old man with end-stage renal disease (ESRD) undergoing transurethral resection of a bladder tumor experienced severe and prolonged hypotension after receiving oral 5-aminolevulinic acid (5-ALA). Continuous infusions of norepinephrine and vasopressin ultimately resolved the hypotension over the course of 26 hours. It is uncertain whether 5-ALA is causative or is a contributing factor that influences other factors, such as hypovolemia after hemodialysis and autonomic nerve dysfunction associated with ESRD. Our findings suggest that anesthesiologists should be aware of the possible occurrence of hypotension after administration of 5-ALA, and urologists should consider intravesical 5-ALA administration in patients with ESRD.	bladder
Bacillus Calmette-Guérin (BCG) therapy lowers the incidence of Alzheimer's disease in bladder cancer patients.	BACKGROUND: Alzheimer's disease (AD) affects one in ten people older than 65 years. Thus far, there is no cure or even disease-modifying treatment for this disease. The immune system is a major player in the pathogenesis of AD. Bacillus Calmette-Guérin (BCG), developed as a vaccine against tuberculosis, modulates the immune system and reduces recurrence of non-muscle invasive bladder cancer. Theoretical considerations suggested that treatment with BCG may decrease the risk of AD. We tested this hypothesis on a natural population of bladder cancer patients. METHODS AND FINDINGS: After removing all bladder cancer patients presenting with AD or developing AD within one-year following diagnosis of bladder cancer, we collected data on a total of 1371 patients (1134 males and 237 females) who were followed for at least one year after the diagnosis of bladder cancer. The mean age at diagnosis of bladder cancer was 68.1 years (SD 13.0). Adjuvant post-operative intra-vesical treatment with BCG was given to 878 (64%) of these patients. The median period post-operative follow-up was 8 years. During follow-up, 65 patients developed AD at a mean age of 84 years (SD 5.9), including 21 patients (2.4%) who had been treated with BCG and 44 patients (8.9%) who had not received BCG. Patients who had been treated with BCG manifested more than 4-fold less risk for AD than those not treated with BCG. The Cox proportional hazards regression model and the Kaplan-Meier analysis of AD free survival both indicated high significance: patients not treated with BCG had a significantly higher risk of developing AD compared to BCG treated patients (HR 4.778, 95%CI: 2.837-8.046, p = 4.08x10-9 and Log Rank Chi-square 42.438, df = 1, p = 7.30x10-11, respectively). Exposure to BCG did not modify the prevalence of Parkinson's disease, 1.9% in BCG treated patients and 1.6% in untreated (Fisher's Exact Test, p = 1). CONCLUSIONS: Bladder cancer patients treated with BCG were significantly less likely to develop AD at any age than patients who were not so treated. This finding of a retrospective study suggests that BCG treatment might also reduce the incidence of AD in the general population. Confirmation of such effects of BCG in other retrospective studies would support prospective studies of BCG in AD.	bladder